MGCD0103, a selective histone deacetylase inhibitor, coameliorates oligomeric Aβ_25‐35‐induced anxiety and cognitive deficits in a mouse model

Abstract

Summary Aims Recently, histone deacetylase ( HDAC ) inhibitors are considered a possible therapeutic strategy in Alzheimer's disease ( AD ). However, HDAC i treatments exhibit diverse functions with unfavorable effects in AD . Thus, the development of selective HDAC i without side effects is urgently needed. Methods HDAC i, namely, BML 210, MGCD 0103, PXD 101, and Droxinostat, were screened in mouse hippocampal primary cultures incubated with oligomeric Aβ 25‐35 (50 μmol/L). MGCD 0103 was chosen for in vivo tests and was intraperitoneally injected into C57 BL /6J mice (0.5 mg/kg, once per day) for 4 weeks following an intrahippocampal CA 1 injection of oligomeric Aβ 25‐35 . Brain samples were collected for pathological analyses after the behavioral analyses including open‐ field test ( OFT ), elevated plus maze ( EPM ), Y‐maze, and Morris water maze ( MWM ). Results Among the HDAC i, MGCD 0103 exhibited significant neuroprotection against the Aβ toxicity in primary cultures. MGCD 0103 coattenuated cognitive deficits and anxiety against Aβ damage in mice. MGCD 0103 further ameliorated pathological features such as the levels of acetylated histone 3 at Lys 9 site (H3K9) and α‐tubulin, synaptophysin, Aβ, tau protein phosphorylation, and serotonergic neuron loss against Aβ toxicity. Furthermore, chronic MGCD 0103 treatment did not show liver or kidney toxicity in mice. Conclusions These results reveal MGCD 0103 could be a potential therapeutic agent against AD .

Administration of Momordica charantia Enhances the Neuroprotection and Reduces the Side Effects of LiCl in the Treatment of Alzheimer’s Disease

“…During the experimental period, the combination of MC5523 and LiCl greatly increased the mouse survival rate against the lethal threat of LiCl in the STZ-treated group ( p < 0.05; Figure 1B). LiCl has been reported to increase apoptosis in liver tissue [38]; therefore, we examined whether the survival benefit of MC5523 was associated with the hepatotoxicity induced by LiCl (i.p.) in the icv-STZ OVX 3×Tg-AD mice.…”

“…The Y maze testing was performed as previously described [38] using an apparatus with three equal arms (35 cm long × 5 cm wide × 15 cm high) made of white acrylic. After the handling adaptation, the mice were individually placed at the center of the maze and allowed to explore for 8 min ( n = 12–15 per group).…”

HDACi protects against vascular cognitive impairment from CCH injury via induction of BDNF‐related AMPA receptor activation

“…HDACi has also been shown to reduce Aβ deposition and block GSK-3β in AD animal models, thereby promoting the recovery of cognitive function. 22,23 In our previous study, the administration of HDACi during CCH almost completely reversed these effects. 1 Moreover, HDACi has been shown to stimulate cell proliferation and the production of new neurons in the adult hippocampus, 24 which may help reduce the observed hippocampal atrophy of CCH-injected mice.…”

“…HDACi can mitigate the progression of neurodegenerative diseases by inhibiting oxidative stress and neuroinflammation. HDACi has also been shown to reduce Aβ deposition and block GSK‐3β in AD animal models, thereby promoting the recovery of cognitive function 22,23 . In our previous study, the administration of HDACi during CCH almost completely reversed these effects 1 .…”

Biochemical and Behavioral Characterization of IN14, a New Inhibitor of HDACs with Antidepressant-Like Properties

“…Epigenetic mechanisms involving chromatin-modifying enzymes have been implicated in the pathophysiology of mental and neurodegenerative diseases such as depression, anxiety and cognitive deficits [1][2][3][4][5], as well as in the therapeutic mechanisms of some antidepressants [6][7][8][9][10][11][12]. Amongst epigenetic mechanisms, histone acetylation-the addition of an acetyl group in the N-terminal lysine residues in the nucleosomal core of histone proteins [13,14]-has been highly implicated in neuroplasticity [15].…”